Fadrozole (marketed as Afema by Novartis) for the treatment of breast cancer.

 

Fadrozole (INN, marketed as Afema by Novartis) is an aromatase inhibitor^[1] that has been introduced in Japan for the treatment of breast cancer.

It is selective.^[2]

1. Raats JI, Falkson G, Falkson HC (January 1992). "A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer". J. Clin. Oncol. 10 (1): 111–6. PMID 1530798.
2. Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A (February 1991). "Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease". J. Med. Chem. 34 (2): 725–36.doi:10.1021/jm00106a038. PMID 1825337.

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer and ovarian cancer inpostmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men.

Aromatase is the enzyme that synthesizes estrogen. As breast and ovarian cancers require estrogen to grow, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors.

Types of AIs

There are 2 types of aromatase inhibitors (AIs) approved to treat breast cancer:

• Irreversible steroidal inhibitors, such as exemestane (Aromasin), forms a permanent and deactivating bond with the aromatase enzyme.

• Non-steroidal inhibitors, such as anastrozole (Arimidex), inhibit the synthesis of estrogen via reversible competition for the aromatase enzyme.

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. The main source of estrogen is the ovaries inpremenopausal women, while in post-menopausal women most of the body's estrogen is produced in peripheral tissues (outside the CNS), and also a few CNS sites in various regions within the brain. Estrogen is produced and acts locally in these tissues, but any circulating estrogen, which exerts systemic estrogenic effects in men and women, is the result of estrogen escaping local metabolism and spreading to the circulatory system.

Cancer drug tested in pet dogs is now bound for human trials

PAC 1
Thanks to a new $2 million investment, a drug that spurs cancer cells to self-destruct while sparing healthy cells is on the road to human clinical trials. The compound, known as PAC-1, has so far proven safe and has promising anti-cancer effects in cell culture, in mouse models of cancer and in pet dogs with spontaneously occurring lymphomas and osteosarcomas.

If PAC-1 (pack one) makes it through the U.S. Food and Drug Administration’s Investigational New Drug review, the first human (Phase I) clinical trial of the drug will begin in mid-2014. The investor, who wishes to remain anonymous, has an option to invest another $2 million to take the drug into human trials. The clinical work will be conducted at the University of Illinois Cancer Center in Chicago.

http://news.illinois.edu/news/13/0717cancer_drug_PaulHergenrother_TimFan.html

Photo by
L. Brian Stauffer

---

University of Illinois chemistry professor Paul Hergenrother, left, and veterinary clinical medicine professor Tim Fan led a study of an anti-cancer compound in pet dogs that is now headed for human clinical trials.
PAC-1 (first procaspase activating compound) is a synthesized chemical compound that selectively induces apoptosis, or cell suicide, in cancerous cells. PAC-1 has shown good results in mouse models and is being further evaluated for use in humans. In 2010 a published study showed PAC-1 to be safe to research dogs, and a second study published later that same year reported that a PAC-1 derivative (called S-PAC-1) was well tolerated in a small Phase I Clinical Trial of pet dogs with lymphoma. Even at low doses of S-PAC-1, tumors regressed in 1/6 dogs, and the disease was stabilized (no additional tumor growth) in 3/6 dogs

Alkermes Adds Multiple Sclerosis Pill To Expanding Pipeline

Alkermes Adds Multiple Sclerosis Pill To Expanding PipelineTheStreet.comThe company expects to seek permission from FDA to begin human testing of its MMF prodrugs for multiple sclerosis in 2014, with a phase I study slated to begin mid-year. Composition of matter patents have been filed, which if granted, would give the ...

read all at
http://www.thestreet.com/story/11981784/1/alkermes-adds-multiple-sclerosis-pill-to-expanding-pipeline.html?cm_ven=GOOGLEN

Santarus Completes Patient Enrollment in CONTRIBUTE Study with UCERIS (budesonide) as Add-on Treatment to 5-ASA Drugs

Santarus Completes Patient Enrollment in CONTRIBUTE Study with UCERIS ...MarketWatchA Biologics License Application for RUCONEST for the treatment of acute angioedema attacks in patients with hereditary angioedema is under review by the U.S. Food and Drug Administration with a response expected in April 2014. Santarus is also ...

read all at


http://www.marketwatch.com/story/santarus-completes-patient-enrollment-in-contribute-study-with-uceris-budesonide-as-add-on-treatment-to-5-asa-drugs-2013-07-18

SAN DIEGO, Jul 18, 2013 (BUSINESS WIRE) -- Santarus, Inc. /quotes/zigman/91852/quotes/nls/snts SNTS -0.61% today announced the completion of enrollment in the CONTRIBUTE clinical study designed to evaluate the incremental benefit of adding UCERIS(R) (budesonide) extended release 9 mg tablets to oral aminosalicylate (5-ASA) therapy for the induction of clinical remission in adult patients with active, mild to moderate ulcerative colitis. UCERIS is currently approved in the U.S. for the induction of remission in patients with active, mild to moderate ulcerative colitis.

Sanofi starts dengue vaccine production for 2015 launch

Sanofi Pasteur is poised to produce the first validation batches of their dengue vaccine at the company’s state-of-the-art production centre near Lyon, France.

According to Antoine Quin, manager at the site in Neuville-sur-Saone, the plant has a design capacity of 100 million doses of the vaccine, tetravalent CYD-TDV, annually. Starting around 2015, Sanofi Pasteur expects to manufacture one billion doses over the following decade.

Investing 300 million euros in building and staffing the plant was a substantial gamble for Sanofi, said Guillaume Leroy, dengue vaccine head. The Lyon facility got the green light in 2009, when only Phase II data was available. Although promising, this was far from definitive........................

read all at

http://www.pharmatimes.com/Article/13-07-15/Sanofi_starts_dengue_vaccine_production_for_2015_launch.aspx

more on dengue

Dengue Fever Prevention

Neither vaccine nor drugs for preventing infection are available. The bite of one infected mosquito can result in infection. The risk of being bitten is highest during the early morning, several hours after daybreak, and in the late afternoon before sunset. However, mosquitoes may feed at any time during the day. Aedes mosquitoes typically live indoors and are often found in dark, cool places such as in closets, under beds, behind curtains, and in bathrooms. Travelers should be advised to use insecticides to get rid of mosquitoes in these areas and to select accommodations with well-screened windows or air conditioning when possible. Additionally, travelers should take measures to avoid being bitten by mosquitoes. Long-term travelers and expatriates can take extra precautions to reduce mosquito-breeding sites around their accommodations by emptying and cleaning or covering any standing water (such as in water storage tanks and flowerpot trays).

SOURCE: CDC

Dengue fever facts

• Dengue fever is a disease caused by a family of viruses that are transmitted by mosquitoes.
• Symptoms such as headache, fever, exhaustion, severe joint and muscle pain, swollen glands (lymphadenopathy), and rash. The presence (the "dengue triad") of fever, rash, and headache (and other pains) is particularly characteristic of dengue fever.
• Dengue is prevalent throughout the tropics and subtropics. Outbreaks have occurred recently in the Caribbean, including Puerto Rico, the U.S. Virgin Islands, Cuba, and in Paraguay in South America, and Costa Rica in Central America.
• Because dengue fever is caused by a virus, there is no specific medicine or antibiotic to treat it. For typical dengue fever, the treatment is purely concerned with relief of the symptoms (symptomatic).
• The acute phase of the illness with fever and myalgias lasts about one to two weeks.
• Dengue hemorrhagic fever (DHF) is a specific syndrome that tends to affect children under 10 years of age. It causes abdominal pain, hemorrhage (bleeding), and circulatory collapse (shock).
• The prevention of dengue fever requires control or eradication of the mosquitoes carrying the virus that causes dengue.
• There is currently no vaccine available for dengue fever.

What is dengue fever?

Dengue (pronounced DENG-gay) can affect anyone but tends to be more severe in people with compromised immune systems. Because it is caused by one of four serotypes of virus, it is possible to get dengue fever multiple times. However, an attack of dengue produces immunity for a lifetime to that particular serotype to which the patient was exposed.Dengue fever is a disease caused by a family of viruses that are transmitted by mosquitoes. It is an acute illness of sudden onset that usually follows a benign course with symptoms such as headache,fever, exhaustion, severe muscle and joint pain, swollen glands(lymphadenopathy), and rash. The presence (the "dengue triad") of fever,rash, and headache (and other pains) is particularly characteristic of dengue. Other signs of dengue fever include bleeding gums, severe pain behind the eyes, and red palms and soles.

Dengue goes by other names, including "breakbone" or "dandy fever." Victims of dengue often have contortions due to the intense joint andmuscle pain, hence the name breakbone fever. Slaves in the West Indies who contracted dengue were said to have dandy fever because of their postures and gait.

Dengue hemorrhagic fever is a more severe form of the viral illness. Symptoms include headache, fever, rash, and evidence of hemorrhage in the body. Petechiae (small red or purple splotches or blisters under the skin), bleeding in the nose or gums, black stools, or easy bruising are all possible signs of hemorrhage. This form of dengue fever can be life-threatening and can progress to the most severe form of the illness, dengue shock syndrome.

Traditional Chinese medicine - chemistry and application

Traditional Chinese medicine - chemistry and application

Amongst the many aspects of modern Chinese chemistry described in the Journal of Chemical Research during 2012, are phytochemical investigations into the constituents of traditional Chinese medicines derived from plants and fungi. Such studies have afforded new medicines to treat diseases such as Alzheimer’s, malaria and cancer.

http://www.sciencereviews2000.co.uk/blog/view/journal-of-chemical-research/58/traditional-chinese-medicine-chemistry-and-application/671

Top Selling Schizophrenia Drug Abilify (Aripiprazole)

 

Aripiprazole (brand names: Abilify, Aripiprex, OPC-14597,) is an atypical antipsychotic drug with the chemical name 7-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy]-3,4-dihydro-2(1H)-quinolinone. It was first discovered by the Otsuka Pharmaceutical Company, Ltd., based in Japan, and in collaboration with Bristol-Myers Squibb began to market the drug in the United States following the approval by the Food and Drug Administration for schizophrenia in November 2002. According to IMS Health, Abilify was the fourth top-selling drug in the United States in 2011, with sales of $5.2 billion.

Chemical Structure of Aripiprazole (brand names: Abilify)

Chemical Synthesis of Aripiprazole(active ingredient for Abilify)

Experimental Procedures for the preparation of Aripiprazole (Abilify)

US 5,006,528 discloses process for the preparation of Aripiprazole in two steps. The first step comprises synthesis of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (7-BBQ) by alkylating the hydroxy group of 7-hydroxy-3,4-dihydrocarbostyril (7-HQ) with 1 ,4-dibromobutane using potassium carbonate in water at reflux temperature for 3 hours to obtain 7-BBQ in 68% yield. The resulting 7-BBQ is further reacted with 1- (2,3-dichlorophenyl)-piperazine to obtain Aripiprazole.

Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)quinolinone (7-(4-bromobutoxy)-3,4-dihydrocarbostyril; 7-BBQ)

7-Hydroxy-3,4-dihydro-2(1H)-quinolinone (aka 7-Hydroxy-3,4-dihydrocarbostyril, 60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40- 45°C for 24 hours. Reaction mass was cooled upto room temperature and was filtered off. The resulting filtrate was distilled off under vacuum. The resultant mass was cooled to 25-30°C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The solid was filtered and dried under vacuum at 55-60°C for 20 hours to obtain title compound. mp 110.5-111 °C; 1H NMR (DMSO-d6) ä 1.81 (2H, m, -CH2-), 1.95 (2H, m, -CH2-), 2.41 (2H, t, J ) 7 Hz, -CH2CO-), 2.78 (2H, t, J) 7 Hz, -CH2-C-CO-), 3.60 (2H, t, J ) 6 Hz, -CH2Br), 3.93 (2H,t, J ) 6 Hz, O-CH2-), 6.43 (1H, d, J ) 2.5 Hz), 6.49 (1H, dd, J) 2.5, 8 Hz), 7.04 (1H, d, J ) 8 Hz), 9.98 (1H, s, NHCO). Anal. (C13H16NO2Br) C, H, N.

Yield: 73-75%; Purity: 93-95%

Preparation of Aripiprazole (7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one)

7-(4-Bromobutoxy)-l ,2,3,4-tetrahydroquinolin-2-one (50 gm) was taken in acetonitrile (500 ml) at 25-30°C. To this potassium carbonate (67.2 gm) and l-(2,3- dichlorophenyl) piperazine hydrochloride (44.9gm) were added under stirring. The reaction mixture was refluxed at 80-85°C for 8 hours. The reaction mass was cooled to room temperature, filtered and the resulting solid was washed with acetonitrile. To the resulting solid, water was added and was stirred. The solid was filtered off, washed with water and dried under vacuum at 75-80°C for 15 hrs. The resulting crude aripiprazole was crystallized from isopropyl alcohol and water to obtain title compound. Yield: 75-80%; Dimer Impurity: <0.1%. 1H NMR: DMSO-d6 d 9.96 [1H, s, NH]; 7.29 [2H, m, Ar]; 7.13 [1H, q, Ar]; 7.04 [1H, d, Ar]; 6.49 [1H, dd, Ar]; 6.45 [1H, d, Ar]; 3.92 [2H, t, -CH2-O-]; 2.97 [4H, bb,2(-CH2-)]; 2.78 [2H, t, -CH2-N2-)]; 2.39 [4H, m, 2(-CH2-)]; 1.73 [2H, m, - CH2-]; 1.58 [2H, m, -CH2-]. IR:cm-1 3193; 2939; 2804; 1680; 1627; 1579; 1520; 1449; 1375; 1270; 1245; 1192; 1169; 1045; 965; 649; 869; 780; 712; 588.

Preparation of aripiprazole anhydrous Type I using isopropyl alcohol and water

Crude aripiprazole (30 g) was taken in isopropyl alcohol (600 ml) and was heated to 80-85°C. Water (90 ml) was added at the same temperature. Activated carbon was added and the mixture was stirred for 30 minutes at the same temperature. The resulting hot solution was filtered and the bed was washed with hot isopropyl alcohol. The resulting filtrate was cooled to 25-30°C for 4 hours. The resulting solid was filtered, washed with isopropyl alcohol and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105°C for 6 hours to obtain title compound.

Yield: 87-89% HPLC Purity: 99.89

Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.

Hydrate A: Below detectable limit (BDL) at limit of detection 1 %.

Particle size distribution: d₁₀=15.83 m, d₅₀=60.12 m, d₉₀=144.99 m

Preparation of aripiprazole anhydrous Type I using ethanol and water

Crude aripiprazole (15 g) was taken in ethanol (300 ml) and water (45 ml) and was heated to 80-85°C for 1-2 hours. The resulting mixture was cooled to 25-30°C within 4 hours and stirred for 3 hours. The resulting solid was filtered and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105°C for 3 hours to obtain title compound. Yield: 90% HPLC Purity: 99.9%

Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.

Hydrate A: Below detectable limit (BDL) at limit of detection 1%.

Particle size distribution: d₁₀=22.01 m, d₅₀=105.10 m, d₉₀=232.97 m

References For the Process of Aripiprazole (Abilify,)

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi, Tatsuyoshi Tanaka, Tetsuro Kikuchi, Katsura Tottori, Yasufumi Uwahodo, and Takao Nishi; Novel Antipsychotic Agents with Dopamine Autoreceptor Agonist Properties: Synthesis and Pharmacology of 7-[4-(4-Phenyl-1-piperazinyl)butoxy]- 3,4-dihydro-2(1H)-quinolinone Derivatives; J. Med. Chem. 1998, 41, 658-667

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi; Carbostyril derivatives, Otsuka Pharmaceutical Co., Ltd; US patent 5006528;Issue date: Apr 9, 1991

BANDO, Takuji, YANO, Katsuhiko, FUKANA, Makoto, AOKI, Satoshi ;Method for producing fine particles of aripiprazole anhydride crystals b; OTSUKA PHARMACEUTICAL CO., LTD., WO 2013002420 A1

ZHENG Siji, LIU Xiaoyi, FU Linyong, TAN Bo, ZHOU Min: ARIPIPRAZOLE MEDICAMENT FORMULATION AND PREPARATION METHOD THEREFOR. / FORMULATION DE MÉDICAMENT ARIPIPRAZOLE ET SON PROCÉDÉ DE PRÉPARATION. / SHANGHAI ZHONGXI PHARMACEUTICAL January 2013: WO 2013/000391

CN 201210235157

CN102846543A

CN102850268A;

CN101781246A 

GUPTA, Vijay Shankar, KUMAR, Pramod, VIR, Dharam ;Process for producing aripiprazole in anhydrous type i crystals;JUBILANT LIFE SCIENCES LIMITED;WO 2012131451 A1

SRIVASTAVA JAYANT GUPTA Vijay Shankar;Improved process for the preparation of 7.(4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole;wo2011030213 A1

No Generic Abilify in the US until April 2015

On May 7, 2012, The U.S. Court of Appeals for the Federal Circuit ruled in favor of Otsuka Pharmaceutical Co., Ltd. in its patent litigation against several companies including Israel-based Teva and Weston, Ontario-based Apotex seeking FDA approval to market generic copies of Abilify®. (see the pdf file for the decision upholding the Otsuka patent here). The Federal Circuit affirmed a decision of the U.S. District Court for the District of New Jersey holding that the asserted claims of U.S. Patent No. 5,006,528 (pdf file here) covering aripiprazole, the active ingredient in Abilify®, are valid, thus maintaining patent and regulatory protection for Abilify® in the U.S. until at least April 20, 2015. The case is Otsuka Pharma Co. v. Sandoz Inc., 2011-1126 and 2011-1127, U.S. Court of Appeals for the Federal Circuit (Washington). The lower court case is Otsuka Pharmaceutical Co. v. Sandoz Inc., 07cv1000, U.S. District Court for the District of New Jersey (Trenton).

Chemical Name for Aripiprazole(active ingredient for Abilify): 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
CAS number 129722-12-9

Aripiprazole  brand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation class of atypical antipsychotics with additional antidepressant properties that is primarily used in the treatment ofschizophrenia, bipolar disorder, major depressive disorder, and irritability associated with autism.^[1] It was approved by the U.S.Food and Drug Administration (FDA) for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007;^[2] and to treat irritability in children with autism on 20 November 2009.^[3] Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amine:

1.  U.S. Patent 5,006,528